Clinical Trial Explores New Frontier in CAR-T Cell Therapy for Lymphoma
Published
Duke Cancer Institute is participating in a national clinical trial that could reshape the future of CAR T-cell therapy for patients with aggressive lymphoma. Led by industry sponsors and involving multiple institutions, the ALPHA3 trial investigates the potential of allogeneic CAR T-cell treatments to prevent relapse in high-risk patients who appear to be in remission following initial chemotherapy.
Traditional CAR-T therapies use a patient’s own T-cells, known as autologous CAR T-cells, which are genetically modified to target and destroy cancer cells. While effective, this process is complex, time-consuming, and can cause significant side effects due to the intensity of the immune response.
The ALPHA3 trial takes a different approach. Instead of relying on a patient’s own cells, it uses donor-derived allogeneic CAR T-cells. These cells are manufactured in bulk, frozen, and ready for use, offering a faster, potentially less toxic alternative. However, because these cells are foreign to the patient’s body, they are often eliminated by the immune system within weeks, limiting their window of effectiveness.
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Results from ALPHA3 could offer new hope for patients with hard-to-treat lymphomas and redefine how remission is maintained.
ALPHA3 is also unique in its focus on patients who are in remission but still at high risk of relapse. After completing chemotherapy, participants undergo a highly sensitive test for measurable residual disease (MRD), a “needle in a haystack” test capable of detecting one cancer cell among millions. If MRD is detected, patients are randomized to receive either allogeneic CAR-T therapy or standard monitoring.
“The hope is that the allogeneic CAR-T will have enough potency to kill off the small number of cancer cells that are hiding in a deep, dark place in the body,” said Mitchell Horwitz, MD, cellular therapy specialist with DCI’s Hematologic Malignancies and Cellular Therapy disease program.
For patients, the trial offers a chance to gain deeper insight into their post-treatment status and potentially receive an intervention that could prevent relapse. From a provider’s perspective, the trial could pave the way for broader use of allogeneic CAR-T therapies.
This multisite trial is highly selective, requiring patients to meet strict criteria for disease risk and MRD positivity.
While early in its implementation, this trial represents a promising evolution in CAR-T therapy.
“These allogeneic CAR-T therapies could be cheaper, quicker to obtain, and less toxic than autologous CAR-T products,” Horwitz said.
A team at the Duke Cancer Institute (DCI) is launching a first-of-its-kind study that could bring new hope to patients living with advanced colorectal cancer.Led by medical student Cheryl Chang and DCI medical oncologist Nicholas DeVito, MD, the project explores why some colorectal cancers that spread to the liver respond well to chemotherapy while others do not. The team recently presented this research at the American Association for Cancer Research (AACR) Immuno-Oncology (IO) Conference.This type of cancer can be especially challenging to treat. Patients often face fewer effective options, and outcomes can vary widely. By taking a closer look at what’s happening inside the tumor before and after treatment, the Duke team hopes to uncover clues that could one day guide more personalized and more effective care.When colorectal cancer spreads to the liver at the time of diagnosis, it often means a tougher road ahead. Doctors know that these patients typically do not respond to chemotherapy the same way others do, but the reasons behind that difference remain unclear.“If we can understand why some patients don’t respond well, we may be able to adjust treatment earlier, or develop new options altogether,” Chang said.To do this, the team is studying tissue samples taken from patients before treatment, when the cancer is first discovered, and after about six months of chemotherapy, when surgeons remove part of the liver or colon.Looking at these pairs of samples gives researchers a rare opportunity to see how cancer and the immune system around it changes during treatment.This is the first known study to compare liver metastasis samples before and after chemotherapy in this specific patient group. Despite decades of using chemotherapy to treat colorectal cancer, surprisingly little is known about how treatment affects the immune environment inside these tumors.“This is an area that’s been largely unexplored,” DeVito said. “We’re excited to contribute something new that has the potential to change how we approach treatment.”A big focus of the study is the tumor microenvironment, the community of immune cells, cancer cells, and other structures within and around each tumor. Using two advanced technologies, the team examines the tumor at both the protein and RNA levels.Working with John Hickey, PhD, assistant professor of biomedical engineering at the Pratt School of Engineering, the team employed the Codex assay in the study. By using special antibodies to highlight different cell types, the assay lets researchers map where various immune cells are and how close they are to the tumor.The team also partnered with Erika Crosby, PhD, assistant professor in the Duke Department of Surgery, to use the Xenium assay, which analyzes the RNA within cells. This helps confirm the protein‑level findings while revealing additional details that might not show up at the protein stage.Early results show meaningful differences between patients who respond to chemotherapy and those who don’t. Some immune cells appear in higher numbers in people who respond well, suggesting these may serve as early indicators of how effective chemotherapy might be.“Without this collaboration between surgery and biomedical engineering, locating and reviewing patient records and samples would have been far more time‑consuming,” DeVito said. “Everything came together at the right time: the technology, the expertise, and access to the right samples. That’s what makes a project like this possible.”A major boost for this work also came from CRUSH Colorectal Cancer, which supports early‑stage ideas that need initial funding before they can compete for larger grants.“CRUSH provided the seed funding that allowed us to get started,” DeVito said. “An added benefit is that any data generated becomes a shared resource for the entire GI oncology team at Duke.”Looking ahead, the team plans to expand their research into mouse models in collaboration with Jatin Roper, MD, that mimic how colorectal cancer spreads to the liver. This could help them test the biomarkers they discover and explore new treatment strategies in the lab.“Ultimately, everything we’re doing comes back to the patient,” Chang said. “We want to find better ways to treat this cancer, especially for patients who don’t have many options today.”The annual CRUSH Colorectal Cancer 5K will be held on March 14. Learn more about the event.
A team at the Duke Cancer Institute (DCI) is launching a first-of-its-kind study that could bring new hope to patients living with advanced colorectal cancer.Led by medical student Cheryl Chang and DCI medical oncologist Nicholas DeVito, MD, the project explores why some colorectal cancers that spread to the liver respond well to chemotherapy while others do not. The team recently presented this research at the American Association for Cancer Research (AACR) Immuno-Oncology (IO) Conference.This type of cancer can be especially challenging to treat. Patients often face fewer effective options, and outcomes can vary widely. By taking a closer look at what’s happening inside the tumor before and after treatment, the Duke team hopes to uncover clues that could one day guide more personalized and more effective care.When colorectal cancer spreads to the liver at the time of diagnosis, it often means a tougher road ahead. Doctors know that these patients typically do not respond to chemotherapy the same way others do, but the reasons behind that difference remain unclear.“If we can understand why some patients don’t respond well, we may be able to adjust treatment earlier, or develop new options altogether,” Chang said.To do this, the team is studying tissue samples taken from patients before treatment, when the cancer is first discovered, and after about six months of chemotherapy, when surgeons remove part of the liver or colon.Looking at these pairs of samples gives researchers a rare opportunity to see how cancer and the immune system around it changes during treatment.This is the first known study to compare liver metastasis samples before and after chemotherapy in this specific patient group. Despite decades of using chemotherapy to treat colorectal cancer, surprisingly little is known about how treatment affects the immune environment inside these tumors.“This is an area that’s been largely unexplored,” DeVito said. “We’re excited to contribute something new that has the potential to change how we approach treatment.”A big focus of the study is the tumor microenvironment, the community of immune cells, cancer cells, and other structures within and around each tumor. Using two advanced technologies, the team examines the tumor at both the protein and RNA levels.Working with John Hickey, PhD, assistant professor of biomedical engineering at the Pratt School of Engineering, the team employed the Codex assay in the study. By using special antibodies to highlight different cell types, the assay lets researchers map where various immune cells are and how close they are to the tumor.The team also partnered with Erika Crosby, PhD, assistant professor in the Duke Department of Surgery, to use the Xenium assay, which analyzes the RNA within cells. This helps confirm the protein‑level findings while revealing additional details that might not show up at the protein stage.Early results show meaningful differences between patients who respond to chemotherapy and those who don’t. Some immune cells appear in higher numbers in people who respond well, suggesting these may serve as early indicators of how effective chemotherapy might be.“Without this collaboration between surgery and biomedical engineering, locating and reviewing patient records and samples would have been far more time‑consuming,” DeVito said. “Everything came together at the right time: the technology, the expertise, and access to the right samples. That’s what makes a project like this possible.”A major boost for this work also came from CRUSH Colorectal Cancer, which supports early‑stage ideas that need initial funding before they can compete for larger grants.“CRUSH provided the seed funding that allowed us to get started,” DeVito said. “An added benefit is that any data generated becomes a shared resource for the entire GI oncology team at Duke.”Looking ahead, the team plans to expand their research into mouse models in collaboration with Jatin Roper, MD, that mimic how colorectal cancer spreads to the liver. This could help them test the biomarkers they discover and explore new treatment strategies in the lab.“Ultimately, everything we’re doing comes back to the patient,” Chang said. “We want to find better ways to treat this cancer, especially for patients who don’t have many options today.”The annual CRUSH Colorectal Cancer 5K will be held on March 14. Learn more about the event.
